1. Field of the Invention
This invention relates to novel compounds and their pharmaceutical formulations, and their uses to treat atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress.
2. Background Information
Treatment of solid mammalian tumors with ionizing radiation involves the in situ generation of hydroxyl radicals and other reactive oxygen species that, due to the focusability of the ionizing radiation are primarily located in the tumor, i.e., in tumor cells. These reactive species possess extreme oxidizing properties which oxidize biomolecules in vivo thereby interfering with cellular metabolism, as discussed by Buettner, et al., Radiation Research, Catalytic Metals, Ascorbate and Free Radicals: Combinations to Avoid, 145:532–541 (1996).
Tumor treatment via the use of ionizing radiation can be enhanced by increasing the radio sensitivity of the tumor cells. One method suggested for enhancing radio sensitivity has been the external administration of a compound having a high affinity for electrons, which ideally localizes in the tumor. Proposed radiation sensitizers include compounds such as halogenated pyrimidines, nitroimidazoles and gadolinium (III) complexes of the pentadentate macrocycle Texaphyrin, as described by Sessler, et al., J. Phys. Chem. A, One-Electron Reduction and Oxidation Studies of the Radiations Sensitizer Gadolinium (III) Texaphyrin (PCI-120) and Other Water Soluble Metallotexaphyrins, 103: 787–794 (1999).
Texaphyrins are known to be useful as radiation sensitizers, and also for the treatment of plaque caused by atherosclerosis, retinal diseases, for the destruction of retroviruses, especially HIV and the like.
Efficacy of texaphyrins is dependent on its ability to penetrate cellular membranes and thereby increase its intracellular concentration. Thus intracellular availability of texaphyrin is a key to its biological activity and effectiveness. Texaphyrins are known to penetrate cell membranes and are known to have an effective intracellular concentration to have beneficial biological activity. An improvement in the ability of a drug substance to enter cellular membranes is however always welcome. It has been surprisingly discovered that premixing texaphyrins with an oxalate salt or an oxalate precursor, for example ascorbic acid, gives rise to a compound whose structure differs from that of a Texaphyrin, but is seen to accumulate more rapidly in tumor cells, plaque, etc.